Abstract
Members of the Plasmodium falciparum Erythrocyte Membrane protein 1 (PfEMP1) family expressed on the surface of malaria-infected erythrocytes mediate binding of the parasite to different receptors on the vascular lining. This process drives pathologies, and severe childhood malaria has been associated with the expression of particular subsets of PfEMP1 molecules. PfEMP1 are grouped into subtypes based on upstream sequences and the presence of semi-conserved PfEMP1 domain compositions named domain cassettes (DCs). Earlier studies have indicated that DC5-containing PfEMP1 (DC5-PfEMP1) are more likely to be expressed in children with severe malaria disease than in children with uncomplicated malaria, but these PfEMP1 subtypes only dominate in a relatively small proportion of the children with severe disease. In this study, we have characterised the genomic sequence characteristic for DC5, and show that two genetically different parasite lines expressing DC5-PfEMP1 bind PECAM1, and that anti-DC5-specific antibodies inhibit binding of DC5-PfEMP1-expressing parasites to transformed human bone marrow endothelial cells (TrHBMEC). We also show that antibodies against each of the four domains characteristic for DC5 react with native PfEMP1 expressed on the surface of infected erythrocytes, and that some of these antibodies are cross-reactive between the two DC5-containing PfEMP1 molecules tested. Finally, we confirm that anti-DC5 antibodies are acquired early in life by individuals living in malaria endemic areas, that individuals having high levels of these antibodies are less likely to develop febrile malaria episodes and that the antibody levels correlate positively with hemoglobin levels.
Highlights
WHO has estimated annual malaria mortality to around 655.000, but this number has been challenged by a recent study estimating malaria mortality to around 1.240.000 [1,2]
We have previously shown that antibody levels to a 3D7 group A var gene encoded PfEMP1 (PF11_0008) containing domain cassette 5 (DC5), are associated with protection from malaria fever and that these antibodies are acquired in early childhood or following a single experimental infection [19,39,40]
The domain cassette 5 (DC5)-PfEMP1 was previously identified as a C-terminal four-domain cassette found in nine group A PfEMP1 sequences present in six of the seven nearcomplete sequenced P. falciparum genomes as well as in the sequenced genome of P. reichenowi [29]
Summary
WHO has estimated annual malaria mortality to around 655.000, but this number has been challenged by a recent study estimating malaria mortality to around 1.240.000 [1,2]. Parasites causing severe malaria are thought to express PfEMP1 that are superior in their ability to sequester due to high binding affinities to their endothelial cell ligands, which causes higher effective in vivo multiplication rates Parasites expressing such PfEMP1 are thought to dominate infections early in life where immunity to these variants has not yet been acquired [12]. This would explain why individuals in areas with intense transmission experience severe malaria symptoms during childhood, but continue to harbour parasites causing uncomplicated disease as they become adults. We elicited anti-PfEMP1 antibodies in rats in order to demonstrate the possibility of inducing cross-reactive antibodies to DC5-PfEMP1 variants
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